Clinical management of chronic pain, including pain related to temporomandibular disorders (TMD), has been challenging in part because a considerable number of chronic pain patients have accompanying psychological and psychiatric comorbidities in which depression is a major contributing factor. While clinical depression has long been linked to chronic pain and antidepressants are commonly used in chronic pain management, the mechanisms underlying the comorbidity between depression and chronic pain remain unclear. To date, there has been a lack of preclinical models that co-express depression and orofacial pain behaviors in same animals. Our recent experiments showed that TMD pain behaviors induced by complete Freund's adjuvant were exacerbated in a subset of Wistar-Kyoto (WKY) rats, a genetic variant of Wistar rats with demonstrable depression behavior, as compared with normal Wistar rats absent of depression behavior. Moreover, melatonin administered into the anterior cingular cortex prevented the exacerbation of TMD pain behaviors with a concurrent improvement of depression behavior in WKY rats. These preliminary results suggest that comparing pain behaviors in animals with and without depression behavior could be a useful approach to investigate the relationship between depression and chronic pain and to explore new treatment options for both depression and chronic pain. Thus, the goals of this application are 1) to explore and evaluate animal models that co-express orofacial pain and depression behaviors and 2) to use the animal model and a new pharmacological approach to examine whether improving depression behavior would result in a concurrent reduction of pain behaviors. We will use behavioral and pharmacological tools, in situ hybridization, immunocytochemistry, Western blot, real-time RT-PCR, and enzyme-linked immunosorbent assay to accomplish three specific aims: 1) to explore and evaluate animal models of combined depression and TMD pain behaviors; 2) to examine the effects of melatonin on depression and TMD pain behaviors; and 3) to examine changes in the melatonin level and brain melatonin receptor expression in relation to depression and TMD pain behaviors. The successful completion of this work will provide important information on a new preclinical model that could be used to examine interactions between depression and chronic pain and to search for novel therapeutic strategies for treating both chronic pain and depression. [unreadable] [unreadable] [unreadable]